Chagas disease is caused by Trypanosoma cruzi and is a major cause of morbidity and mortality in many areas of Latin America ranging from the Southern United States to Argentina. Up to 30 to 40% of those infected will ultimately have some degree of cardiac involvement which is the leading cause of cardiovascular death in areas where the disease is endemic. Although not common in the United States there are estimated to be more than 100,000 infected persons residing in the United States, however and it has been suggested that cases will be encountered in increasing numbers. The heart is the most severely and affected organ; however, the pathogenesis of virtually all aspects of Chagas' disease continues to elude our understanding. An understanding of the molecular mechanisms involved in parasite proliferation in the mammalian host could provide the basis for developing strategies to control T. cruzi infection. Recent studies from our laboratory have shown that epidermal growth factor (EGF) binds specifically and selectively to the amastigote form of T. cruzi, that two monoclonal antibodies to the mammalian EGF receptor interact with a distinct surface protein of T. cruzi and that EGF stimulates growth of amastigotes both within and outside host cells. The long term objective of this proposal is to understand the mechanisms by which EGF modulates T. cruzi growth in mammalian host cells. The specific goal of this proposal is to study aspects of the interaction of EGF with its receptor on amastigotes and to begin to elucidate the signal transduction pathways induced by this growth factor on amastigotes. To this end we propose: a) to study signal transduction events that occur after EGF binds to its receptor on the parasite surface; b) to study the internalization and down regulation of the EGF receptor in T. cruzi amastigotes following ligand binding; c) to study the ability of other factors belonging to the EGF family to bind and induce proliferation of amastigote forms of T. cruzi; d) to follow the internalization pathways of EGF receptor in a T. cruzi infected cell. These studies have the potential to elucidate novel mechanisms by which T. cruzi exploits pathways normally available to host cells to establish itself intracellularly. The fact that amastigotes have a growth factor receptor homologue provides an unique model to understand growth regulation of intracellular human pathogens. In the long run, an identification of such novel mechanisms is necessary to develop molecular means to control T. cruzi infection and other infectious diseases.